Although leprosy(Hansen's disease) is one ofthe oldestknown diseases, the pathogenicity of Mycobacterium leprae (M. leprae) remains enigmatic. Indeed, the cellwall components responsible for the... Show moreAlthough leprosy(Hansen's disease) is one ofthe oldestknown diseases, the pathogenicity of Mycobacterium leprae (M. leprae) remains enigmatic. Indeed, the cellwall components responsible for the immune response against M. leprae are as yet largely unidentified. We reveal herephenolic glycolipid-III (PGL-III) as an M. leprae-specific ligand for the immune receptor Mincle. PGL-III is a scarcelypresent trisaccharide intermediate in the biosynthetic pathway toPGL-I, an abundant and characteristic M. leprae glycolipid.Using activity-based purification, we identified PGL-III as a Mincleligand that is more potent than the well-known M. tuberculosis trehalose dimycolate. The cocrystal structure of Mincle and a syntheticPGL-III analogue revealed a unique recognition mode, implying thatit can engage multiple Mincle molecules. In Mincle-deficient miceinfected with M. leprae, increased bacterial burdenwith gross pathologies were observed. These results show that PGL-IIIis a noncanonical ligand recognized by Mincle, triggering protectiveimmunity.PGL-III, a potent immunostimulatory glycolipid,is limitedin M. leprae by the quick addition of a single methylgroup to convert it into immunosuppressive PGL-I, which confers immuneescape. Show less
Multi-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable... Show moreMulti-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable performance between populations of European and East Asian ancestries.Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 x 10(-8)), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA. Show less
